The hypothalamo-pituitary-adrenal axis (HPA) plays an important role in the relationship between the immune and neuroendocrine systems. Blunting of the HPA response to stress enhances susceptibility to or severity of inflammatory/autoimmune disease. The cascade of HPA hormones released under stress conditions may exert a dampening role on specific defense mechanisms, especially on most cellular actions of the inflammatory immune response. Cytokines, polypeptide mediators, classically associated with immune system regulation and inflammation, play a significant role in the HPA axis activation during immune disorders and actively mediate signaling between the immune and endocrine systems. Leukemia inhibitory factor (LIF), a pleotropic cytokine with diverse biologic activities, also present in pituitary corticotrophs, stimulates proopiomelanocortin (POMC) gene transcription, and is significantly induced in mouse hypothalamus and pituitary in response to endotoxin. As LIF is an inducible proinflammatory hypothalamo-pituitary cytokine which may function as a paracrine regulator of ACTH we hypothesize that LIF is involved in control of the inflammatory/autoimmune process acting through regulation of the HPA axis. Preliminary studies conducted in LIF knockout mice, and shown herein, demonstrate that in the absence of LIF, mice cannot maintain an appropriate level of HPA axis activation in response to stress and exogenous IL 1. In addition, the low HPA response to mycobacterial adjuvant observed in knockout animals compared to normal littermates shows a strong correlation between LIF-regulated activity of the HPA axis and susceptibility to inflammatory process. In this study we will determine the molecular and physiological mechanisms implicating LIF in the neuroendocrine control of inflammation. We will utilize both in vivo whole animal models as well as in vitro molecular techniques to characterize the role of LIF in mediating HPA axis response to pathological stress. The hypothesis that LIF mediates the HPA axis response to acute inflammatory challenges as well as to experimental (experimental allergic encephalomyelitis) and genetically determined (systemic lupus erythematosus) inflammatory/autoimmune disease will be tested. This study will provide insights into the cytokine-mediated neuro-immuno-endocrine interface.